Correction of the Iron Overload Defect in β-2-Microglobulin Knockout Mice by Lactoferrin Abolishes Their Increased Susceptibility to Tuberculosis
Open Access
- 25 November 2002
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 196 (11), 1507-1513
- https://doi.org/10.1084/jem.20020897
Abstract
As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. β-2-microglobulin (β2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)–restricted CD8 T cells in protection against M. tuberculosis. However, β2m associates with a number of MHC-I–like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, β2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in β2m–KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I–KO mice. In parallel, the generation of nitric oxide impaired in β2m–KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of β2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.Keywords
This publication has 32 references indexed in Scilit:
- Lactoferrin Peptide Increases the Survival of Candida albicans - Inoculated Mice by Upregulating Neutrophil and Macrophage Functions, Especially in Combination with Amphotericin B and Granulocyte-Macrophage Colony-Stimulating FactorInfection and Immunity, 2001
- HFE—A Novel Nonclassical Class I Molecule that Is Involved in Iron MetabolismImmunity, 2000
- Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human MacrophagesInfection and Immunity, 2000
- Lactoferrin: A multifunctional glycoproteinAPMIS, 1999
- Why intracellular parasitism need not be a degrading experience forMycobacteriumPhilosophical Transactions Of The Royal Society B-Biological Sciences, 1997
- Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.The Journal of Experimental Medicine, 1996
- Exochelins of Mycobacterium tuberculosis remove iron from human iron-binding proteins and donate iron to mycobactins in the M. tuberculosis cell wall.The Journal of Experimental Medicine, 1996
- A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells.The Journal of Experimental Medicine, 1995
- Iron overload in β2-microglobulin-deficient miceImmunology Letters, 1994
- Regulation of transferrin receptor expression and ferritin content in human mononuclear phagocytes. Coordinate upregulation by iron transferrin and downregulation by interferon gamma.JCI Insight, 1993